It is estimated that nearly 20% of US troops deployed in Iraq and Afghanistan conflicts have suffered probable traumatic brain injury (TBI). Among survivors, the loss of circulating levels of testosterone (hypogonadism) is one of the most frequently reported deficits and the long-term effects of dramatically increase the risk of multiple symptoms including PTSD, depression, anxiety and cognitive loss. The e4 allele of apolipoprotein E is the strongest risk factor for developing Alzheimer's disease and is also associated with a worsened outcome following TBI. Importantly, individuals who carry APOE4 are 10X more likely to develop AD compared to those without the allele. Given that both TBI and testosterone loss adversely impact neurophysiology, the purpose of this study is to test the hypothesis that APOE genotype and testosterone interact to increase the risk of brain injury and that hormone replacement may significantly improve outcome. Using a mouse model that expresses human apoE proteins, we will use a closed head injury model to assess the effects of testosterone loss and TBI on behavioral outcomes and neuronal structure and function (Aim 1). We will next assess the effects of hormone replacement on these outcomes (Aim 2). As there are currently no effective treatments that improve outcome following TBI, hormone replacement may provide a potential therapeutic option to attenuate the onset of mental and cognitive disorders that result from hypogonadism, especially in veterans who are genetically at risk.